Down to the bone: Understanding how bone-dissolving cells are generated
Scientists explain the role of a certain protein in the generation of
cells critical to bone maintenance

Date:
June 9, 2020
Source:
Tokyo University of Science
Summary:
Bone-dissolving cells called osteoclasts are derived from a type
of immune cells called macrophages. They are necessary for the
maintenance and renewal of bones. But the intracellular mechanisms
through which macrophages convert to osteoclasts are not fully
understood. Recently, scientists have uncovered the role of a
protein called Cpeb4 in this process. Their findings suggest
potential therapeutic targets for bone and joint diseases like
arthritis and osteoporosis.



FULL STORY ========================================================================== Chronic bone and joint diseases, such as osteoporosis and rheumatoid
arthritis, affect millions of people worldwide, particularly the
elderly, degrading their quality of life. An important factor in both
of these diseases is the excessive activity of bone-dissolving cells
called osteoclasts. Osteoclasts are formed through differentiation from a certain type of immune cell called macrophage, after which they acquire
their new role in the maintenance of bones and joints: breaking down
bone tissue to allow osteoblasts-another type of cell-to repair and
remodel the skeletal system.


========================================================================== Broadly, two intracellular processes are involved in this differentiation: first, transcription-in which a messenger RNA (mRNA) is created from the genetic information in DNA-and then, translation-in which the information
in the mRNA is decoded to produce proteins that perform specific
functions in the cell. Since the discovery of the role of a particular
protein called RANKL in osteoclast formation, scientists have solved
a considerable portion of the puzzle of which cell signaling pathways
and transcription networks regulate osteoclast generation. Yet, the post-transcription cellular processes involved remain to be understood.

Now, in a new study published in Biochemical and Biophysical
Research Communications, scientists at Tokyo University of Science,
Japan, unraveled the role of a protein called Cpeb4 in this complex
process. Cpeb4 is part of the "cytoplasmic polyadenylation element
binding (CPEB)" family of proteins, which bind to RNA and regulate translational activation and repression, as well as "alternative splicing" mechanisms that produce protein variants. Dr Tadayoshi Hayata, who led
the study, explains: "CPEB proteins are implicated in various biological processes and diseases, such as autism, cancer, and red blood cell differentiation. However, their functions in osteoclast differentiation
are not clearly known. Therefore, we conducted a series of experiments to characterize a protein from this family, Cpeb4, using cell cultures of
mouse macrophages." In the various cell culture experiments conducted,
mouse macrophages were stimulated with RANKL to trigger osteoclast differentiation and the evolution of the culture was monitored. First, the scientists found that Cpeb4 gene expression, and consequently the amount
of Cpeb4 protein, increased during osteoclast differentiation. Then,
through immunofluorescence microscopy, they visualized the changes in
the location of Cpeb4 within the cells. They found that Cpeb4 moves from
the cytoplasm into nuclei, while presenting specific shapes (osteoclasts
tend to fuse together and form cells with multiple nuclei).

This indicates that the function of Cpeb4 associated with osteoclast differentiation is likely carried out inside the nuclei.

To understand how RANKL stimulation causes this Cpeb4 relocalization,
the scientists selectively "inhibited" or represses some of the proteins
that become involved "downstream" in the intracellular signaling pathways triggered by the stimulation. They identified two pathways as necessary
for the process.

Nonetheless, further experiments will be required to fully learn about
the sequence of events that takes place and all the proteins involved.

Finally, Dr Hayata and his team demonstrated that Cpeb4 is absolutely
necessary for osteoclast formation using macrophage cultures in which
Cpeb4 was actively depleted. The cells in these cultures did not undergo further differentiation to become osteoclasts.

Taken together, the results are a stepping stone to understanding the
cellular mechanisms involved in osteoclast formation. Dr Hayata remarks:
"Our study sheds light on the important role of the RNA-binding protein
Cpeb4 as a positive "influencer" of osteoclast differentiation. This gives
us a better understanding of the pathological conditions of bone and joint diseases and may contribute to the development of therapeutic strategies
for major diseases like osteoporosis and rheumatoid arthritis." Hopefully,
the deeper level of understanding of osteoclast generation facilitated
by this study will ultimately translate into improved quality of life
for people living with painful bone and joint diseases.


========================================================================== Story Source: Materials provided by Tokyo_University_of_Science. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yasuhiro Arasaki, Masamichi Li, Takuro Akiya, Iori Nozawa,
Yoichi Ezura,
Tadayoshi Hayata. The RNA-binding protein Cpeb4 is a novel positive
regulator of osteoclast differentiation. Biochemical and Biophysical
Research Communications, 2020; DOI: 10.1016/j.bbrc.2020.05.089 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200609111054.htm

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